Duchenne muscular dystrophy is the most common and devastating of the muscular dystrophies. The only effective therapy to date is chronic use of corticosteroids, yet patients respond variably to treatment and the basis of this benefit is not understood. The theme of the proposed Center application is to increase our understanding of the pathophysiology of Duchenne muscular dystrophy at multiple complementary yet interacting levels. The proposed research projects propose to break down the complex disease pathophysiology into component biochemical pathways, each of which shows evidence of cross-talk. This cross-talk in pathways leads to a synergism of projects and expertise in the proposed Center. Project 1 proposes to study genetic modifiers of Duchenne dystrophy, taking advantage of extensive patient resources available through the Cooperative International Neuromuscular Research Group (CINRG). This is the "clinical project" for the Center. Project 2 studies cell damage and remodeling pathways as. a function of age and disease progression in human patients, with pathophysiological models tested in transgenic mice. Project 3 studies the issues of satellite cell characterization and activation as a function of age in the mdx mouse model. The proposed Center is centered in the Research Center for Genetic Medicine, a interdisciplinary group of -70 scientists with a major focus on the muscular dystrophies at all levels from clinics, clinical trials, molecular biology, and ethics. The three proposed projects are supported by three Cores;an Administrative Core, a Human Clinical Core (CINRG), and a Bioinformatics and Computing Core. This Center application has been extensively revised to respond to the previous critiques, including new published manuscripts addressing technical concerns regarding feasibility. The key personnel of the proposed Center (Drs. Hoffman, Escolar, Partridge, Chen, Nagaraju, Pegoraro, Leshner) have continued their strong publication record in neuromuscular disease and the topics of the proposal, with 129 manuscripts over the last 5 years, including 18 co-authored by two or more key personnel. ]